There are many ways to slice the “lymphoma pie”

Simplified classification of NHLs Indolent (low grade) Aggressive (intermediate grade) Highly aggressive (high grade) Certain types may not fit cleanly into one of these categories (such as grade 3A follicular lymphoma – can behave as “indolent” in some cases and “aggressive” in others) In some cases an indolent lymphoma can “transform” into a more aggressive lymphoma

3 Classification of NHL Based on Tumor Behavior Indolent NHL – Low grade – Associated with slow disease progression. May not need treatment for years. – Can see prolonged survival even with partial response to therapy – Usually incurable by standard therapy FL (gr 1-2), MZL, LPL, SLL Mantle cell? Grade 3A FL? Aggressive NHL – Intermediate grade – Rapid growth and may be fatal within months if untreated – Can be cured with intensive therapy – Only patients who achieve complete response are cured DLBCL, FL 3B, most T cell NHLs Mantle cell? Grade 3A FL? Highly aggressive NHL – High grade – Generally requires treatment within days to weeks – Can be cured with intensive therapy (only if complete response attained) Burkitt, Lymphoblastic “Double hit” lymphoma ? Skarin and Dorfman. CA Cancer J Clin. 1997;47:351.

But nothing is ever that simple…

Some lymphomas don’t fit into one category… One type of lymphoma can change into another (transformed) Some lymphomas have features of 2 types – “grey zone”: features that overlap two types – “composite” two different lymphomas mixed together

How much disease does the patient have? STAGING

7 How is the stage of lymphoma determined? Does it matter? Stage does matter somewhat in terms of prognosis – However, compared to most other cancers, stage has a much smaller effect on prognosis – Example: if lung cancer changes from stage I to IV, difference between curable and not – For HL, stage I-A 90-95% cured with first-line therapy; stage IV-B about % cured with first line therapy – For DLBCL, stage I-A 80+ % cured; stage IV-B about 50-60% cured depending on other factors Stage plays a role in selection of treatment, especially for HL and DLBCL

12 How is the stage of lymphoma determined? Does it matter? Stage does matter somewhat in terms of prognosis – However, compared to most other cancers, stage has a much smaller effect on prognosis – Example: if lung cancer changes from stage 1 to 4, difference between curable and not – For HL, stage I-A 90-95% cured with first-line therapy; stage IV-B about % cured with first line therapy – For DLBCL, stage I-A 80+ % cured; stage IV-B about 50-60% cured depending on other factors Stage plays a role in selection of treatment, especially for HL and DLBCL For most NHLs, type of lymphoma, prognostic score, and response to treatment are more important that stage alone

How will the patient do? PROGNOSIS Many of the more common lymphomas have unique prognostic scoring systems (DLBCL, FL, MCL, PTCL, CLL/SLL, HL) For some lymphomas, more sophisticated “molecular” profiling can now identify subtypes (i.e., DLBCL) Will discuss more in breakout sessions

14 How is lymphoma treated? There is a wide range of treatments Depends on: – The type of lymphoma – The goal of treatment – The age and condition of the patient In general, surgery is NOT part of the treatment Treatments are usually – Chemotherapy – Immunotherapies (rituximab) – Radiation – Novel agents – Blood / marrow transplantation

Conventional chemotherapy Madagascar rosy periwinkle (vincristine) First patient ever treated with chemotherapy was a NHL patient in 1942 (nitrogen mustard) Goodman LS et al, JAMA 1946

Castel del Monte Constructed in the 1240s by Emperor Frederick II In 1950s, a new strain of Streptomyces peucetius isolated – red pigment

Monoclonal antibodies: a special type of protein made by B cells and plasma cells Light chain Heavy chain Variable region Antigen binding region “Targeting” region “Triggering” region

18 Proposed Mechanisms of Action for mAbs CDC Recruit immune cells Punch holes in cell ADCC Recruit immune cells Apoptosis “direct killing”

Monoclonal antibody therapies

20 Brentuximab vedotin

How does radiation work? Radiation damages DNA in both normal and malignant cells SIZE and DOSE of radiation field affect side effects Role of radiation in lymphoma is shifting

“Targeted” therapies

Autologous stem cell transplantation

25 Can lymphoma be cured? What does remission mean? When does remission = cure?

Remission versus Cure Life-threatening Causing symptoms No symptoms, but still detectable Not detectable = REMISSION Level of Disease Early Relapse Cure Time All 3 patients started with the same level of disease Late Relapse Diagnosis treatment All 3 achieved complete remission One relapsed early, one relpased late, one was cured Only time can tell who is who (unless testing improves) How much time until remission = cure? Is cure even possible? Depends on the disease and the treatment given

Remission versus Cure Life-threatening Causing symptoms No symptoms, but still detectable Not detectable = REMISSION Level of Disease Cure Time Diagnosis treatment Highly aggressive 1 yr Aggressive 5 yrs Indolent 10+ yrs?? Remission = cure when enough time has gone by such that relapse is no longer seen (based on prior studies for type of lymphoma with that treatment)

Lymphoma Overview - Summary A complex family of blood cancers A good biopsy (accurate diagnosis) is CRITICAL for management We are just beginning to understand why lymphomas develop Staging and prognosis are important parts of the overall management There are MANY new treatments that are based on better science Listen, learn, and ask questions!

SUPPLEMENTAL SLIDES

6/28/06 8/22/06 85 yo F presented with weight loss, weakness, splenomegaly, INR 3.1 (off coumadin). Treated with 4 infusions of Rituxan, with dramatic improvement in energy and PO intake.

31 1/25/065/14/06 47 yo male, presented with fatigue, night sweats, diffuse bone pains. Biopsy showed Diffuse large B-cell lymphoma Treated with RCHOP-14 (6 cycles), and 6 intrathecal prophylactic injections (of methotrexate and cytarabine). Achieved complete response.

32 1/19/051/25/05 23 yo M presented with acute SOB, hypoxia. Found to have supraclav LAD and mediastinal mass  Lymphoblastic Lymphoma. Treated with cytoxan, daunorubicin, vincristine, prednisone and L-asparaginase.

Follicular lymphoma (low grade; indolent)

Burkitt lymphoma (highly aggressive; high grade)

Hodgkin lymphoma

37 RITs in the Treatment of NHL 90 Y Radionuclide Chelator Ibritumomab Tiuxetan Tositumomab 131 I radioisotope